Objective

The I-MOVE+ Consortium includes European Union (EU) Public Health Institutes, SME and Universities. It aims at measuring and comparing the effectiveness (VE) and impact (VI) of influenza and Pneumococcal vaccines and vaccination strategies a in the elderly population in Europe. The goal is to develop a sustainable platform of primary care practices, hospitals and laboratory networks that share validated methods to evaluate post marketing vaccine performances. The objectives are to identify, pilot test, and disseminate in EU the best study designs to measure, on a real time basis, VE (direct effect) and the VI of vaccination programmes (indirect and overall effect) against laboratory confirmed cases of influenza (types/subtypes) and pneumococcal disease (serotypes), and clinical outcomes. Cost effectiveness analysis will be conducted.

Results will allow to understand factors affecting specific VE, the duration of protection of influenza and pneumococcal vaccines, the interaction between vaccines, the role of repeated vaccinations, the occurrence of serotype replacement (pneumococcus); identify vaccine types and brands with low VE; guide the decision of the WHO committees on vaccine strain selection (influenza); provide robust benefit indicators (VE and VI) and cost benefit and effectiveness results; guide vaccination strategies (schedules, doses, boosters). This EU member state collaboration will respond to questions that require studies based on large sample sizes and sharing of expertise that cannot be achieved by one country alone. It will allow the best methods to be used and results to benefit to all EU countries whatever their current public health achievements. Results will be shared with international partners.

Periodic Reporting for period 3 - I-MOVE-plus (I-MOVE+ Integrated Monitoring of Vaccines Effects in Europe: a platform to measure and compare effectiveness and impact of influenza and pneumococcal vaccines and vaccination strategies in the elderly)

The I-MOVE+ (Integrated Monitoring of Vaccines in Europe) is a consortium of 29 European Union/European Economic Area (EU/EEA) partners (regional and national public health Institutes, SME, Universities). Its goal is to develop a sustainable platform of primary care, hospital and laboratory networks in the EU/EEA that can share and use validated standardised methods to serve the post marketing evaluation of existing and new vaccines programmes independently from commercial interests.I-MOVE+ is based on a multi-country multidisciplinary network of clinicians, epidemiologists, laboratory specialists, statisticians, modellers and economists from a network of 16 EU/EEA Member States.

We measured at primary care and hospital level, early and late in the season, the direct effect (effectiveness) and indirect effect of various types of influenza vaccines against laboratory confirmed (PCR positive) outcomes

We measured the effectiveness of available vaccines and the impact of pneumococcal vaccination programmes against laboratory confirmed (serotype specific) cases of invasive pneumococcal disease (IPD) and a core set of clinically defined outcomes (pneumonia). We provided evidence on the occurrence and magnitude of serotype replacement following introduction of conjugate vaccination.

The cost-effectiveness of various vaccination strategies were measured.

The results from the hospital and primary care networks suggest moderate to low influenza VE amongt those aged 65 years and over, At primary care level, VE ranged from 13% to 66% against A(H1N1)pdm09, from - 9% to 15% against A(H3N2) and from 9% to 27% against influenza B. VE against hospitalised influenza was 39% (95% CI: 17 to 56) against A(H1N1)pdm09 in 2015/16, 17% (95% CI: 1 to 31) against A(H3N2) in 2016/17, and, in 2017/18, was 24% (95%CI: 3 to 41) against A(H3N2) and 31% (95%CI: 17 to 42) against influenza B. The low vaccination coverage in this age group resulted in imprecise estimates. The impact studies underlined that, even with a sub-optimal vaccine effectiveness, influenza vaccination prevent cases in primary and secondary care and deaths amongst those aged 65 years and over. The effect of previous vaccinations and natural immunity should be further studied in long term and larger studies to guide vaccination strategies in this population.

WP3: - Generic protocols for effectiveness and impact of studies of pneumococcal vaccines - Five sites have conducted feasibility studies on pneumonia using hospital discharge database- Survey on data available for analyses relating to the role of influenza vaccination on IPD; feasibility studies conducted by six sites

We used a before/after study to measure the impact of childhood vaccination on the incidence of IPD, pneumococcal pneumonia and all-cause pneumonia in 65+ years age group.Compared with 2009 (n=13 sites), the all-type IPD incidence decreased by 8% (95%CI: -5-9) in 2015, by 7% (-6-9) in 2016 and by 3% (-12-5) in 2017. Compared to the expected incidence based on pre-vaccination trends (n=4 sites), the incidence of pneumococcal pneumonia decreased after PCV10/13 introduction (35% (95%CI: 14-51) in age group 65-69 years, 23% (-18-49) in age group 65+ in 2016). The incidence of all-cause pneumonia did not change.PPV23 effectiveness (n=6 sites) was 29% (17-39), overall and ranging 19-48% by high-risk condition type. PPV23 effectiveness was higher when associated with PCV13 vaccination. The results suggest that PPV23 vaccination protects around a third of elderly vaccinated individuals.

The work conducted within WP4 suggest: 1. Using the same database, Influenza VEs was consistently higher in the test-negative design than in the cohort design.2. Similar VE estimates and confidence intervals were obtained when using a traditional covariate adjusted model and a propensity score adjusted model.3. In general, when estimating the effect of previous influenza vaccines no common pattern could be observed within a season between care setting (primary and second care) from the same study site or between study designs (TND and cohort) from the same study site.4. Taking into account either 3 or 5 previous seasons to define a study subjects vaccination history yield similar VE estimates both in the cohort and test-negative design

I-MOVE+ assembled the largest ever network of study sites in the EU/EEA allowing to strengthen evaluation research in vaccinology between Member States. I-MOVE+ independent studies on pneumococcal and influenza vaccines provided evidence for decision making on elderly vaccination.I-MOVE+ underlined the importance of maintaining independent publice funding for evaluating vaccines.

The I-MOVE+ influenza VE results contributed to guidethe WHO vaccine strain selection committee on strains to be included in the influenza vaccines and to increase the number of influenza viruses reported to the European virological surveillance system and WHO Global Flunet.I-MOVE+ articles and communications provided a better understanding of the impact and effectiveness of influenza and pneumococcal vaccines in the elderly.

Deliverables

This will include additional information obtained through deliverables D4.1. The study sites will adapt the generic influenza protocol by describing the study design(s), the outcomes, the settings (GP, hospital based), the types of vaccines, the plan of analysis, the variables that will be included in the analysis and how these are obtained, how previous vaccinations are accounted for etc. The plan of analysis will describe how to measure vaccine effectiveness (direct effect) in the elderly population, including adjustment for confounders by covariates or (if possible) imputations.

Each season, the study sites will adapt the generic protocol by describing the setting in each of the seasons (e.g. vaccines used, start of vaccination campaign, change in the number of GPs participating in the surveillance network, etc).

This will include additional information obtained through deliverables D4.1. The study sites will adapt the generic influenza protocol by describing the study design(s), the outcomes, the settings (GP, hospital based), the types of vaccines, the plan of analysis, the variables that will be included in the analysis and how these are obtained, how previous vaccinations are accounted for etc. The plan of analysis will describe how to measure vaccine effectiveness (direct effect) in the elderly population, including adjustment for confounders by covariates or (if possible) imputations.

At least one scientific article presenting the results of the influenza VE and impact I-MOVE+ studies will be submitted at the end of the season to an open source journal. An abstract will be submitted to the ESCAIDE conference or to any other relevant conference. (Month 18, Month 30, Month 40)

The final pooled VE report will include the results of the multicentre case control studies (primary care and hospital studies) and a summary of the studies conducted within WP4 using electronic databases. The report will include the results of the research questions addressed (effect of previous vaccinations, duration of protection).

At the end of the three year project, a summary article will be written summarising all the lessons learnt, the results of the research questions addressed (effect of previous vaccinations, duration of protection).

At least one scientific article presenting the results of the influenza VE and impact I-MOVE+ studies will be submitted at the end of the season to an open source journal. An abstract will be submitted to the ESCAIDE conference or to any other relevant conference.

The generic protocols will include a description of the study design, the setting(s), the plan of analysis for study site estimates and for pooled estimates, the minimum set of variables to be collected, the sample size.
They will specify the parts that each study site will have to document when writing the study site protocol. The generic protocols will detail the methods used and the plan of analysis to answer to specific research questions such as the effect of previous vaccinations and the duration of protection).

At least one scientific article presenting the results of the influenza VE and impact I-MOVE+ studies will be submitted at the end of the season to an open source journal. An abstract will be submitted to the ESCAIDE conference or to any other relevant conference.

Each season, the study sites will adapt the generic protocol by describing the setting in each of the seasons (e.g. vaccines used, start of vaccination campaign, change in the number of GPs participating in the surveillance network, etc).

The final pooled VE report will include the results of the multicentre case control studies (primary care and hospital studies) and a summary of the studies conducted within WP4 using electronic databases. The report will include the results of the research questions addressed (effect of previous vaccinations, duration of protection).

Written report including a generic cost-effectiveness model which can be used among the participating countries; Depending on the results in task 5.1 and 5.2 the findings will be presented in one or two peer-reviewed publications, Month 24.
As the deliverables of this work package are heavily dependent on the availability of data we want to state that we will try to include as many countries participating in WP2,3 and 4 as possible. Scotland, the Netherlands, Germany and Finland will contribute.

The final pooled VE report will include the results of the multicentre case control studies (primary care and hospital studies) and a summary of the studies conducted within WP4 using electronic databases. The report will include the results of the research questions addressed (effect of previous vaccinations, duration of protection).

The generic protocols will include a description of study designs, the setting(s), the plan of analysis for study site estimates and for pooled estimates, the minimum set of variables to be collected, sample size. They will specify the parts that each study site will have to document when writing the study site protocol. Generic protocols will detail the methods used and the plan of analysis to answer to specific research questions such as the duration of protection, magnitude of replacement etc.

This will include additional information obtained through deliverables D4.1. The study sites will adapt the generic influenza protocol by describing the study design(s), the outcomes, the settings (GP, hospital based), the types of vaccines, the plan of analysis, the variables that will be included in the analysis and how these are obtained, how previous vaccinations are accounted for etc. The plan of analysis will describe how to measure vaccine effectiveness (direct effect) in the elderly population, including adjustment for confounders by covariates or (if possible) imputations.

Scientific manuscript that presents 1) the results from the comparison of influenza VE estimates using different methods on the same database 2) Effect of previous influenza vaccinations on current influenza VE.

A set of training material will be available on the website addressing methodological issues of studies measuring the effects of the influenza vaccine and data analysis. The training material will include presentations, case studies and programmes for data analysis.

The report includes A) Descriptions of influenza outcomes in each database, including detailed information on methods used for detection and subtyping in each county. Description of information on vaccines (product name, repeated vaccination eg) and level of information on risk factors and confounders. B) The comparability of the databases is explored in order to identify a common level of detail of information in the databases, which allows register-based studies across countries.

Each season, the study sites will adapt the generic protocol by describing the setting in each of the seasons (e.g. vaccines used, start of vaccination campaign, change in the number of GPs participating in the surveillance network, etc).

An I-MOVE+ website will be available with three levels of access: restricted to study sites conducting studies and ECDC, restricted to I-MOVE+ partners, and open to public. Study sites will exchange results using the restricted website area. In this restricted area, sites will update on a regular basis the number of individuals recruited in the studies. Preliminary results will be shared among relevant study sites during periodic videoconferences. The website will include a library of documents (protocols, articles, training material, videoconference minutes etc).